Release Date:  August 7, 2000

RFA:  AT-00-004

National Center for Complementary and Alternative Medicine

National Cancer Institute

Letter of Intent Receipt Date:  November 10, 2000
Application Receipt Date:       January 12, 2001



The National Center for Complementary and Alternative Medicine (NCCAM) is 
committed to ensuring that the healthcare profession and the American public 
are provided with the best possible information about the safety and efficacy 
of botanicals. However, there is a paucity of reliable, research-based data 
available to guide choices about the use of botanicals simultaneously with 
over-the-counter and prescription drugs. The widespread usage of botanicals, 
the high probability that botanicals and pharmaceutical drugs are being used 
concomitantly, the generic concern that potential drug-drug interactions 
should always be a cause for caution, and the recently published reports of 
adverse botanical/drug interactions support the need for this initiative.  The 
main objective of this initiative is to encourage biomedical research in order 
to prevent adverse botanical/drug interactions during therapy or anesthesia, 
to establish possible synergistic combinations of botanicals with 
pharmaceutical drugs, and to increase our knowledge of the mechanisms of 
action of botanicals. 


The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Botanical/Drug Interactions, is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government. Racial/ethnic minority individuals, women, 
and persons with disabilities are encouraged to apply as Principal 


This RFA will use the National Institutes of Health (NIH) R01 and the NCCAM 
R21 award mechanisms.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed two years for the R21 applications or three years for the R01 
applications.  This RFA is a one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is August 2001.


The NCCAM intends to commit approximately $4.3 M in FY 2001 to fund ten R21 
and five R01 new and/or competitive continuation grants in response to this 
RFA.  An R21 applicant may request a project period of up to two years and a 
budget for Direct Costs of up to $125,000 per year.  An R01 applicant may 
request a project period of up to three years and a budget for Direct Costs of 
up to $375,000 per year.  Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will also 
vary. Although the financial plans of the NCCAM provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications. At 
this time, it is not known if this RFA will be reissued.



Eisenberg (1998) reported that 18 percent of individuals taking 
prescription drugs were concurrently using herbals or high dose vitamin 
products, or both. They estimated that 15 million adults are at risk for 
potential drug-dietary supplement interactions. The frequency and extent of 
adverse drug reactions or even positive, synergistic efficacy due to 
concurrent use is unknown. Since the Eisenberg study also revealed that fewer 
than 40 percent of those surveyed disclosed their use of complementary and 
alternative medicines to their physicians, the difficulty of gathering 
information about botanical/drug interactions is further compounded. The use 
of anesthetics on patients who are concurrently taking botanicals and other 
supplements may pose acute risks for the patient (Norred and Finlayson, 2000).
Botanical products, as used by the public, are usually complex mixtures. Since 
both the putative active ingredient(s) and other constituents (i.e., "inert" 
ingredients and contaminants) in the mixture have the potential for 
interactions with pharmaceutical drugs or anesthetics, studies of standardized 
botanical products (even when available) may have significant methodological 
limitations. Thus, purified components of botanical products, used singly or 
in combination, may be the most suitable reagents for some studies of 
botanical/drug interactions.  These studies in turn will allow subsequent 
investigations of whole products or unrefined botanical extracts.  Despite the 
experimental difficulties engendered by the relative lack of standardized 
botanicals available as reference reagents, more studies investigating 
botanical/drug interactions are needed immediately to better inform the 
American public and the healthcare profession.  Moreover, since the NCCAM has 
recently initiated Phase III clinical trials to study the efficacy of some 
botanicals (i.e. Ginkgo and Hypericum) that are already in widespread public 
use, and since additional trials with other botanicals are being carried out 
at NCCAM Centers and are being contemplated, there is an imperative for 
additional research on possible botanical/drug interactions.


The proposed initiative is expected to stimulate investigator-initiated 
biomedical research on botanical/drug interactions in vitro, in animal models, 
and in phase I/II or case control clinical studies. The phase I/II clinical 
studies are expected to examine the uptake, bioavailability, or 
pharmacodynamics of the botanical/drug combination in contrast to these 
parameters when the herbal or drug is administered alone.  This RFA invites 
proposals designed to explore the cellular and molecular effects of botanicals 
in interactive paradigms with proprietary drugs, or studies which may help to 
predict the effects of the botanicals on drug action and metabolism in vivo.  
The case control studies should be aimed at elucidating the relationship 
between a botanical product and specific adverse events in the presence of a 
proprietary drug. 


The NCCAM does not usually accept research applications in the botanical 
category that focus on the isolation of active ingredients from herbal 
preparations, except when this is necessary for identification and 
standardization of optimal whole products or when comparisons are being made 
to the complex product or to investigate metabolic pathways and mechanisms of 
action as part of the proposed research project.  Conventional drug discovery 
and drug development approaches using botanicals as the source are not 
considered to be within the scope of this RFA.

Research projects can be basic (mechanistic) and/or clinical studies other 
than a Phase III trial (defined below).  Case control studies WILL be accepted 
in response to this RFA.  Applications that do not meet one or more of these 
requirements will be ineligible for funding.  Health services studies or 
surveys and epidemiological studies except for case control studies WILL NOT 
be accepted under this RFA.  

For the purpose of this RFA, a Phase III trial is defined as a broadly based 
prospective investigation usually involving a substantial number of human 
subjects either at a single site or at multiple sites.  The primary objective 
of such trials is to evaluate an experimental intervention in comparison with 
a standard or control intervention, or to compare two or more existing 
treatments.  In Phase III trials, the primary endpoint is usually a 
significant change in some clinical outcome.  The definition includes 
interventions given for disease prevention, prophylaxis, diagnosis, or 

Research components involving phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous data 
management, quality assurance, and auditing procedures.  In addition, it is 
NIH policy that all clinical trials require data and safety monitoring, with 
the method and degree of monitoring being commensurate with the risks (NIH 
Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, 
June 12, 1998: 
).  The NIH has also released "Further Guidance On A Data And Safety 
Monitoring For Phase I and Phase II Trials", NIH Guide, June 5, 2000:  In 
addition, NCCAM requires that all masked clinical trials, regardless of size, 
establish an independent data and safety monitoring board.  The Data Safety 
Monitoring Guidelines for NCCAM-supported clinical trials are available at: Funds should 
be budgeted for these activities.  They should not duplicate internal review 
and monitoring systems that are already in place at the institution.


It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43

All investigators proposing research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994 (FR 
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 
11, March 18, 1994, and is available on the web at:  


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  Although a letter of 
intent is not required, is not binding, and does not enter into the review of 
a subsequent application, the information that it contains allows NCCAM staff 
to estimate the potential review workload and plan the review.

Mail/Fax letters of intent on or before November 10, 2000 to:

Dr. Neal B. West
Program Officer
National Center for Complementary and Alternative Medicine
Building 31/ Room 5B58
Bethesda, MD  20892-2182
Telephone:  (301) 402-5867
FAX:  (301) 402-4741


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:


The modular grant concept establishes specific modules in which Direct Costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award.  It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted in 

Applicants wishing to submit R21 applications are encouraged to contact the 
Program Staff listed under INQUIRIES prior to submission.  The NCCAM has 
guidelines for the preparation and submission of these applications as 
outlined in R21 APPLICATION GUIDELINES below.  Applications for R21 grants 
that do not meet the requirements as outlined in these guidelines will not be 
accepted by the NCCAM.  


o The purpose of the NCCAM's Exploratory/Developmental Research (R21) grant 
mechanism is to provide investigators, at all career levels, with a funding 
opportunity for exploring the feasibility, as well as the development, of 
projects investigating botanical/drug interactions.  The R21 mechanism is 
specifically intended to support innovative ideas where preliminary data as 
evidence of feasibility are sparse or do not exist. These grants are not 
intended for large-scale undertakings or to support or supplement ongoing 
research. Rather, R21-supported projects are intended to serve as a basis for 
planning and strengthening future investigator-initiated research project 
grant applications (R01). It is important to note that, while originality of 
approach and potential significance of the proposed research are major 
considerations in evaluation for funding R21 grants, the applicant is also 
responsible for presenting the background literature that provides some basis 
for the approach and developing a rigorous research plan.

o For R21 applications, Direct Costs are limited to a maximum of $125,000 per 
year for a maximum of two years.  Direct Costs requested for the proposed 
period may not exceed $250,000.  Direct costs should be requested in 
increments of $25,000.  Total Costs should equal the modular Direct Costs 
plus Facilities and Administrative (F&A) costs.  The award is nonrenewable 
and may not be used to supplement an ongoing project.

o Do not exceed a total of fifteen pages for Items a-d in the Research Plan.  
Tables and figures are included in the page limitation.  Applications that 
exceed the page limitation or NIH requirements for type size and margins 
(refer to PHS 398 application for details) will be returned to the applicant 
without further consideration.  The fifteen-page limitation does not include 
Items e-I (Human Subjects, Vertebrate Animals, Literature Cited, Consortia, 
and Consultants). 

o Color illustrations or original photographs may be included in an Appendix.  
These are allowed only if there are copies of black and white figures 
appearing in the body of the application.  No other appendix material is 

o Applications not following the above instructions will be returned to the 
applicant without review.


Modular Grant applications will request Direct Costs in $25,000 modules, up 
to a total Direct Cost request of $250,000 per year for R01s and $125,000 per 
year for R21s.  Applications that request more than $250,000 direct costs in 
any year must follow the traditional PHS 398 application instructions.  The 
total Direct Costs must be requested  in accordance with the  program 
guidelines and  the modifications made to the standard  PHS 398 application 
instructions described below:

PHS 398
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative  (F&A) costs] for the initial 
budget period Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

of the PHS 398.  It is not required and will not be accepted with the 

categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See for 
sample pages.)  At the top of the page, enter the total Direct Costs 
requested for each year.  This is not a Form page.

o Under Personnel, List ALL project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of Total Costs (direct 
plus Facilities and Administrative) for each year, each rounded to the 
nearest $1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project.  Indicate whether the collaborating institution 
is foreign or domestic.  The Total Cost for a consortium/contractual 
arrangement is included in the overall requested modular Direct Cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at:

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all 
future budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

The title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 

The sample RFA label available at: has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a typewritten, signed original of the application, including the 
Checklist, and four signed photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, one additional copy of the application must be sent 

Dr. Richard L. Nahin
Director, DERTR
National Center for Complementary and Alternative Medicine
9000 Rockville Pike
Building 31, Room 5B58
Bethesda, MD  20892-2182
Telephone: (301) 496-4792
FAX: (301) 402-4741

Applications must be received by January 12, 2001.  If an application is 
received after that date, it will be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique.


Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NCCAM in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and may 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the NCCAM National Advisory Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

Because the exploratory grant mechanism (R21) is designed to support 
innovative ideas, preliminary data as evidence of feasibility of the project 
are not required.  However, the applicant does have the responsibility for 
developing a sound research plan approach, including appropriate statistical 
analyses and sample size calculations where appropriate.   Innovation of the 
project and potential significance of the proposed research will be major 
considerations in the evaluation of this mechanism.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.


Letter of Intent Receipt Date:    November 10, 2000 
Application Receipt Date:         January 12, 2001
Council Review:                   May 2001
Earliest Anticipated Start Date:  August 2001


Award criteria that will be used to make award decisions include: 
o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Neal B. West
Program Officer
National Center for Complementary and Alternative Medicine
Building 31/ Room 5B58
Bethesda, MD  20892-2182
Telephone:  (301) 402-5867
FAX:  (301) 402-4741

Dr. Jeffrey D. White
Director, Office of Cancer Complementary
and Alternative Medicine
National Cancer Institute
Executive Plaza North, Suite 102
National Institutes of Health
Bethesda, MD  20892
phone:  301-435-7980
fax:  301-480-0075

Direct inquiries regarding review issues to:

Dr. Richard L. Nahin
Director, DERTR
National Center for Complementary and Alternative Medicine
9000 Rockville Pike
Building 31, Room 5B58
Bethesda, MD  20892-2182
Telephone: (301) 496-4792
FAX: (301) 402-4741

Direct inquiries regarding fiscal matters to:

Suzanne White*
Grants Operations Branch
National Heart, Lung and Blood Institute
National Institutes of Health
Two Rockledge Center, Suite 7154, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7952
Phone:  301-435-0170
Fax:  301-480-3310

* Note: NHLBI is the Grants Management Service
Center for the NCCAM


This program is described in the Catalog of Federal Domestic Assistance No. 
93.213.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.

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